Perfluoroalkyl and polyfluoroalkyl substances interact with platelet glycoprotein Ibα and exacerbate thrombosis.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are highly stable man-made chemicals. They have recently garnered significant attention due to their ubiquitous presence in the environment and deleterious effects on human health including cardiovascular diseases (CVDs). Thrombosis due to platelet activation is a major aspect in CVDs.

Preventative and therapeutic effects of a novel humanized anti-glycoprotein Ibα fragment of antigen-binding region in a murine model of thrombotic thrombocytopenic purpura.

Background: Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal blood disorder resulting from severe deficiency of plasma ADAMTS-13 activity. Current treatment for immune-mediated TTP includes daily therapeutic plasma exchange plus caplacizumab and immunosuppressives. For hereditary TTP resulting from mutations of ADAMTS-13, plasma infusion or recombinant ADAMTS-13 is the treatment of choice.

Salvianolic acid B inhibits thrombosis and directly blocks the thrombin catalytic site.

Background: Salvianolic acid B (SAB) is a major component of root (Danshen), widely used in East/Southeast Asia for centuries to treat cardiovascular diseases. Danshen depside salt, 85% of which is made up of SAB, is approved in China to treat chronic angina. Although clinical observations suggest that Danshen extracts inhibited arterial and venous thrombosis, the exact mechanism has not been adequately elucidated.

c-Mpl-del, a c-Mpl alternative splicing isoform, promotes AMKL progression and chemoresistance.

Acute megakaryocytic leukemia (AMKL) is a clinically heterogeneous subtype of acute myeloid leukemia characterized by unrestricted megakaryoblast proliferation and poor prognosis. Thrombopoietin receptor c-Mpl is a primary regulator of megakaryopoeisis and a potent mitogenic receptor. Aberrant c-Mpl signaling has been implicated in a myriad of myeloid proliferative disorders, some of which can lead to AMKL, however, the role of c-Mpl in AMKL progression remains largely unexplored.

In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα.

The interaction of platelet GPIbα with von Willebrand factor (VWF) is essential to initiate platelet adhesion and thrombosis, particularly under high shear stress conditions. However, no drug targeting GPIbα has been developed for clinical practice. Here we characterized anfibatide, a GPIbα antagonist purified from snake (Deinagkistrodon acutus) venom, and evaluated its interaction with GPIbα by surface plasmon resonance and in silico modeling.

Coenzyme Q10 attenuates platelet integrin αIIbβ3 signaling and platelet hyper-reactivity in ApoE-deficient mice.

Coenzyme Q10 (CoQ10) exists in a wide variety of foods and has promising cardiovascular benefits. However, its effects on platelets and integrin αIIbβ3 signaling during atherosclerosis have not been previously explored. Here, apolipoprotein E-deficient (ApoE-/-) mice were fed a standard diet, high-fat diet (HFD) or CoQ10-supplemented HFD for 12 weeks.

Coenzyme Q10 Upregulates Platelet cAMP/PKA Pathway and Attenuates Integrin αIIbβ3 Signaling and Thrombus Growth.

Scope: Platelet integrin αIIbβ3 is the key mediator of atherothrombosis. Supplementation of coenzyme Q10 (CoQ10), a fat-soluble molecule that exists in various foods, exerts protective cardiovascular effects. This study aims to investigate whether and how CoQ10 acts on αIIbβ3 signaling and thrombosis, the major cause of cardiovascular diseases.

Apolipoprotein A-IV binds αIIbβ3 integrin and inhibits thrombosis.

Platelet αIIbβ3 integrin and its ligands are essential for thrombosis and hemostasis, and play key roles in myocardial infarction and stroke. Here we show that apolipoprotein A-IV (apoA-IV) can be isolated from human blood plasma using platelet β3 integrin-coated beads. Binding of apoA-IV to platelets requires activation of αIIbβ3 integrin, and the direct apoA-IV-αIIbβ3 interaction can be detected using a single-molecule Biomembrane Force Probe.

Cancer and platelet crosstalk: opportunities and challenges for aspirin and other antiplatelet agents.

Platelets have long been recognized as key players in hemostasis and thrombosis; however, growing evidence suggests that they are also significantly involved in cancer, the second leading cause of mortality worldwide. Preclinical and clinical studies showed that tumorigenesis and metastasis can be promoted by platelets through a wide variety of crosstalk between platelets and cancer cells. For example, cancer changes platelet behavior by directly inducing tumor-platelet aggregates, triggering platelet granule and extracellular vesicle release, altering platelet phenotype and platelet RNA profiles, and enhancing thrombopoiesis.

The integrin PSI domain has an endogenous thiol isomerase function and is a novel target for antiplatelet therapy.

Integrins are a large family of heterodimeric transmembrane receptors differentially expressed on almost all metazoan cells. Integrin β subunits contain a highly conserved plexin-semaphorin-integrin (PSI) domain. The CXXC motif, the active site of the protein-disulfide-isomerase (PDI) family, is expressed twice in this domain of all integrins across species.

Platelets and platelet adhesion molecules: novel mechanisms of thrombosis and anti-thrombotic therapies.

Platelets are central mediators of thrombosis and hemostasis. At the site of vascular injury, platelet accumulation (i.e.

Platelets are versatile cells: New discoveries in hemostasis, thrombosis, immune responses, tumor metastasis and beyond.

Platelets are small anucleate blood cells generated from megakaryocytes in the bone marrow and cleared in the reticuloendothelial system. At the site of vascular injury, platelet adhesion, activation and aggregation constitute the first wave of hemostasis. Blood coagulation, which is initiated by the intrinsic or extrinsic coagulation cascades, is the second wave of hemostasis.

Platelets, immune-mediated thrombocytopenias, and fetal hemorrhage.

Platelets are small versatile blood cells generated from megakaryocytes in the bone marrow and cleared in the reticuloendothelial system. Platelet accumulation (adhesion and aggregation) at the site of injury has been considered the first wave of hemostasis. Interestingly, although fibrinogen and von Willebrand factor (VWF) are documented to be essential for hemostasis, fibrinogen/VWF-independent platelet aggregation and thrombosis still occur.

Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis.

Short-term studies in subjects with diabetes receiving glucagon-like peptide 1 (GLP-1)-targeted therapies have suggested a reduced number of cardiovascular events. The mechanisms underlying this unexpectedly rapid effect are not known. We cloned full-length GLP-1 receptor (GLP-1R) mRNA from a human megakaryocyte cell line (MEG-01), and found expression levels of GLP-1Rs in MEG-01 cells to be higher than those in the human lung but lower than in the human pancreas.